Previous studies associate various microbes with Alzheimer's disease (AD), but the question of whether microbe-related antigens represent a causal component of AD or are an opportunistic passenger of neurodegeneration is difficult to resolve. We propose to expand on our preliminary work mapping biological networks underlying AD-associated phenotypes using independent human post-mortem data sets. First, we apply a computational approach to build region-specific biological networks from `preclinical AD' samples measured from individuals that meet neuropathological criteria for AD, but who were cognitively intact at the time of death. Specifically, we construct regulatory networks from entorhinal cortex (EC) and hippocampal (HIP) tissue and compared the structure of preclinical AD and control networks. Network analysis identified several sub-networks and key drivers perturbed in preclinical AD, including enrichments relevant to viral susceptibility loci among network drivers, including roles for C2H2 zinc fingers, G4-quadruplex activity, and miR-155 in regulating diverse viral factors. Network analysis of a second independent data set characterizing individuals with `clinical AD' identified more direct evidence for network mechanisms of viral activity in AD. The availability of DNA and RNA sequencing allowed us to evaluate the direct presence of viral sequences and quantify association with AD. We observe increased abundance of human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) across multiple regions from subjects with AD compared with controls. We replicated these findings in two additional, independent and geographically dispersed AD cohorts. We built preliminary network models of host- virus regulatory interactions and virus-virus interactions to correlate viral species with the severity of cognitive impairment and neuropathology. We find evidence that the virus-host landscape is shaped by both competitive and synergistic interactions between multiple viral species, with impacts on amyloid precursor protein (APP) processing, cytoskeletal organization, protein synthesis and innate immune response. We identified host DNA variants that associate with viral abundance (vQTL), and that vQTLs associate with increased AD risk, clinical dementia severity, and neuropathology severity, indicating a shared genetic basis linking risk for AD, severity of AD neuropathology, and abundance of specific viral species. We propose to perform computational and experimental work to further elucidate the specific network mechanisms causal drivers or viral pathogens in AD pathophysiology. We aim i) to map and models the roles of specific viral species in modulating pathogenic molecular, genetic, and clinical networks in preclinical and clinical AD, ii) to evaluate the roles of C2H2 zinc finger proteins and G-quadruplex sequences in mediating molecular pathology of preclinical and clinical AD, and iii) to identify and evaluate specific molecules that mediate viral effects upon the molecular pathology of preclinical and clinical AD.